Current approaches to treating cancer aim at attacking the cancer cells by chemical or physical methods (for example, radiation or chemotherapy). More recent approaches aim at reducing the amount of diffusible factors that promote cell growth or at impairing their receptors. These approaches, however, lead to the evolution of resistance [Gorre et al. 2001, Wang et al. 2004, Donnenberg et al. 2005, Kobayashi et al. 2005, Bergers & Hanahan 2008, Ding et al. 2011, Roth et al. 2001] as in the case of antibiotic resistance in bacteria [Merlo et al., 2006, Lambert et al. 2011, Chabner & Roberts 2005]. This is the main reason why mortality rates for cancer have remained almost unaltered for 40 years (chemotherapy and radiotherapy still account for the majority of treatments) [Weinberg 2006, Chabner & Roberts 2005, Siegel et al. 2012].
Therapies select for resistance because cancer is a process of clonal selection within the body on the timescale of an individual's lifetime [Cairns 1975, Nowell 1976]: somatic mutations that enable a clonal lineage to reproduce more rapidly increase in frequency at the expenses of neighbour cells, even if deleterious to the host in the long term [Crespi & Summers 2005, Merlo et al. 2006, Lambert et al. 2011, Greaves & Maley 2012]. For the same reason, mutant cells that happen to be resistant against treatment increase in frequency at the expenses of non-resistant cells, eventually leading to relapse of the disease. In this sense, the problem with current treatments is that they are not “evolutionarily stable”.
What one wants to achieve is a treatment that does not confer an advantage to resistant varieties of cells, and that instead would favour mutants that, increasing in frequency, confer a benefit to the patient. The present invention provides such a method by modifying the dynamics of the production of diffusible factors using cells that do not produce, or produce in low amount, diffusible factors. The invention particularly relates to said cells, which have been modified to reduce the rate or efficacy of the growth factors they produce. Preferably, the cells are modified genetically.
In the course of cancer progression, tumour cells produce growth factors that increase cell survival and proliferation or which promote the maintenance and growth of the cells.
While attacking growth factors or their receptors has recently been attempted as an anti-cancer therapy, it suffers from the same problem as traditional therapies: resistant mutants arise that make the therapy ineffective in the long term. The anti-VEGF drug Avastin, for example, attacks cancer by impairing the growth factor (VEGF) that induces angiogenesis. It is known that anti-VEGF drugs only delay the progression of certain types of cancer by 4 months on average, after which resistance evolves that leads to relapse [Bergers & Hanahan 2008, Amit et al. 2013].
RNA interference uses the same type of approach: it reduces growth factors at the mRNA stage.
In contrast to these previous approaches, the method proposed here does not directly attack the cancer cells, nor directly impairs or reduce the amount of diffusible factors or their receptors.
Instead, the method presented here uses cells that do not produce the diffusible factors, or that produce the diffusible factors in lower amount (“non-producers”, or “low-producers”, or “−/−”) to change the dynamics of the production of diffusible factors, either directly by adding −/− cells to the population, or indirectly by modifying the environment of the cells in ways that confer a selective advantage to −/− cells. Spontaneous clonal selection (competition between cancer cells) will then favour −/− cells allowing them to increase in frequency, or leading to a reduction in the amount of diffusible factors cells produce.
Such −/− cells may arise spontaneously in the cancer cell population (e.g. the tumour) or may be created in laboratory and eventually added to the cancer cell population (e.g. the tumour). Preferably such −/− cells are created in laboratory by modifying existing cancer cells. Preferably the modification is a partial or complete knockout of a gene that codes for, or promotes the production of, one or multiple growth factors. Preferably such −/− are deficient in the production of multiple diffusible factors.
Conditions under which −/− cells have a selective advantage can be brought about by increasing the fraction of −/− cells in the population, for example by introducing an adequate number of −/− cells in the population or by introducing an adequate amount of the factor that has been knocked out from said cells.
While in current and previous approaches mutant cells that are resistant against treatment have a private advantage over non-resistant cells, in the method proposed here mutants that produce a higher amount of diffusible factors (“producers”, “+/+”) will have a disadvantage against −/− cells and therefore the treatment is evolutionarily stable.